In the past two decades, organofluorine compounds have attracted much attention due to their unique properties and unusual reactivities. Among them, trifluoromethyl group (CF3) containing compounds are of particular importance for different applications in the materials field, as well as in the pharmaceutical and agrochemical industries. Although many trifluoromethylation methods are known, such as organometallic, nucleophilic, electrophilic and radical trifluoromethylations, fluoride induced nucleophilic trifluoromethylation with (trifluoromethyl)trimethylsilane (TMS-CF3) previously developed by the present inventors is considered a straightforward, convenient and versatile method. See, Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393; Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757, the content of which is incorporated herein by reference thereto. TMS-CF3 was commonly prepared from ozone-depleting trifluoromethyl halides, but recently, a non-Freon based preparation has been reported. See Prakash, G. K. S.; Hu, J.; Olah, G. A., J. Org. Chem. 2003, 68, 4457, incorporated herein by reference thereto.
Since the 1990s, there has been increasing research interest in trifluoromethylation using trifluoromethane (CF3H) as a trifluoromethylating precursor. CF3H has low toxicity and is not ozone-depleting. It is a side-product of the multi-step industrial synthesis of Teflon.® The efficient production of CF3H has been disclosed via fluorination of methane with hydrogen fluoride and chlorine (Webster J. L.; Lerou, J. J. U.S. Pat. No. 5,446,218, 1995). For example, Shono and co-workers used electrochemically reduced 2-pyrrolidone base to deprotonate CF3H to generate the trifluoromethyl anion equivalent that reacts with aldehydes and ketones (Shono, T.; Ishifume, M.; Okada, T.; Kashimura, S. J. Org. Chem. 1991, 56, 2). Troupel et al. also reported that cathodic reduction of iodobenzene generates a strong base, which deprotonates CF3H, inducing its addition to aldehydes (Barhdadi, R.; Troupel, M.; Perichon, J. Chem. Comm. 1998, 1251). Thereafter, two research groups carried out extensive studies on the nucleophilic trifluoromethylation using CF3H as a precursor. Normant and co-workers have demonstrated the trifluoromethylation of aldehydes by CF3H/potassium dimsylate in DMF (Folleas, B.; Marek, I.; Normant, J.-F.; Saint-Jalmes, L. Tetrahedron Lett. 1998, 39, 2973; Folleas, B.; Marek, I.; Normant, J.-F.; Saint-Jalmes, L. Tetrahedron 2000, 56, 275). They suggested that the CF3−/DMF adduct was the key intermediate in the trifluoromethyl transfer process.
Additionally, Roques, Langlois and co-workers reported the nucleophilic trifluoromethylation of carbonyl compounds and disulfides with CF3H and different bases in DMF. See, (a) Russell, J.; Roques, N. Tetrahedron 1998, 54, 13771. (b) Large, S.; Roques, N.; Langlois, B. R J. Org. Chem. 2000, 65, 8848. (c) Roques, N.; Russell, J.; Langlois, B.; Saint-Jalmes, L.; Large, S. PCT Int. Appl. 1998, WO 9822435. (d) Roques, N.; Mispelaere, C. Tetrahedron Lett. 1999, 40, 6411, each of which are incorporated herein by reference.
CF3−/N-formylmorpholine adduct was also developed as a stable reagent for the trifluoromethylation of non-enolizable carbonyl compounds (Billard, T. B.; Langlois, B. R. Org. Lett. 2000, 2, 2101). Under similar consideration, piperazino hemiaminal of trifluoro-acetaldehyde was also used as a trifluoromethylating agent (Billard, T.; Langlois, B. R.; Blond, G. Eur. J. Org. Chem. 2001, 1467; Billard, T.; Langlois, B. R. J. Org. Chem. 2002, 67, 997; Langlois, B. R.; Billard, T. Synthesis 2003, 185).
Trifluoromethyl iodide (CF3I) has also been successfully used as a nucleophilic trifluoromethylating agent under the activation of electron-donating tetrakis-(dimethylamino)ethylene (TDAE) (Ait-Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W. Jr. Org. Lett. 2001, 3, 4271). Motherwell et al. reported the nucleophilic trifluoromethylation using trifluoromethyl-acetophenone-N,N-dimethyl-trimethylsilylamine adduct (Motherwell, W. B.; Storey, L. J. Synlett 2002, 646). Langlois et al. also have reported nucleophilic trifluoromethylations of non-enolizable carbonyl compounds using trifluoroacetic acid derivatives, trifluoromethanesulfinic acid derivatives and trifluoroacetophenone ((a) Langlois, B. R.; Billard, T. Synthesis 2003, 185. (b) Jablonski, L.; Joubert, J.; Billard, T.; Langlois, B. R. Synlett 2003, 230. (c) Inschauspe, D.; Sortais, J.-P.; Billard, T.; Langlois, B. R. Synlett 2003, 233. (d) Jablonski, L.; Billard, T.; Langlois, B. R. Tetrahedron Lett. 2003, 44, 1055). More recently, a nucleophilic trifluoromethylation method using trifluoroactetamides from amino alcohols was reported (Joubert, J.; Roussel, S.; Christophe, C.; Billard, T.; Langlois, B. R.; Vidal, T. Angew. Chem. Int. Ed. 2003, 42, 3133). Thus, there is a need to develop a convenient and non-ozone depleting reagent for the nucleophilic trifluoromethylation.
Nucleophilic displacement of the trifluoromethyl group has been reported for trifluoromethyl aryl sulfones with sodium methoxide (Shein, S. M.; Krasnopol'skaya, M. I.; Boiko, V. N., Zh. Obshei Khim. 1966, 36, 2141). A similar reaction between trifluoromethyl aryl sulfone and Grignard reagents has been reported for the preparation of sulfones (Steensma, R. W.; Galabi, S.; Tagat, J. R.; McCombie, S. W., Tetrahedron Lett. 2001, 42, 2281). More recently, Cheburkov et al. reported that perfluoroalkyl sulfones react with metal hydroxides in water or alcohol solution and with ammonia to form fluorinated sulfonic acid derivatives (Barrera, M. D.; Cheburkov, Y.; Lamanna, W. M. J. Fluorine Chem. 2002, 117, 13).
A reductive trifluoromethylation using trifluoromethyl sulfides, sulfoxides and sulfones as trifluoromethyl (CF3) group precursors has previously been reported (Prakash, G. K. S.; Hu, J.; Olah, G. A., J. Org. Chem. 2003, 68, 4457). Under reductive conditions when magnesium metal was used, however, the reaction only worked with chlorosilanes as electrophiles, while attempts to react with carbonyl compounds failed.
All of these methods of trifluoromethylation or difluoromethylation have drawbacks. First of all, trifluoromethane is a low-boiling gas (b.p. −84° C.) and its handling as a reagent in the laboratory is not convenient. Second, none of these trifluoromethylations work well with enolizable carbonyl compounds. Thus, there remains a need for a convenient and efficient method for the nucleophilic trifluoromethylation.
Furthermore, due to the unique properties of fluorine atom, more and more organofluorine compounds have been found to have certain biological effects that mimic or block other compounds or that provide polar or lipophilic effects. For instance, C—F bond is known to mimic a C—H bond because of its similar bond length, and difluoromethylene group is known to be isosteric and isopolar to an ethereal oxygen (Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah, G. A. J. Am. Chem. Soc. 1997, 119, 1572–1581; and the references therein). Thus, the synthesis of fluorine-containing analogs of bioactive natural products are of great interest for their potential applications in pharmaceutical industry. Since anti-1,3-diol functionality is a fundamental unit in many naturally occurring compounds, its stereoselective preparation is always attractive to synthetic organic chemists. anti-2,2-Difluoropropan-1,3-diols 3 are a group of interesting compounds, however, not much is known about their synthesis. Currently, the only reported method to synthesize these compounds is via the diasteroselective Meerwein-Pondorff-Verley reduction of α,α-difluoro-β-hydroxy ketones (Kuroboshi, M.; Ishihara, T. Bull. Chem. Soc. Jpn. 1990, 63, 1185–1190). The disadvantage of this approach is the requirement of preparation of α,α-difluoro-β-hydroxy ketones as the precursors. In 1997, the preparation of difluorobis(trimethylsilyl)methane (TMSCF2TMS) as a potential difluoromethylene dianion (“−CF2−”) equivalent was reported (Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah, G. A. J. Am. Chem. Soc. 1997, 119, 1572–1581), but TMSCF2TMS was found only to couple with one molecule of aldehyde such as benzaldehyde to give 2,2-difluoro-1-phenylethanol (after acidic hydrolysis). Thus, there remains a need to develop a synthetic methodology for difluoromethylenation to introduce difluoromethylene dianion species (“−CF2−”) to prepare 2,2-difluoropropan-1,3-diols directly from the carbonyl compounds.